US20170081369A1 - Peptides as oxytocin agonists - Google Patents

Peptides as oxytocin agonists Download PDF

Info

Publication number
US20170081369A1
US20170081369A1 US15/368,080 US201615368080A US2017081369A1 US 20170081369 A1 US20170081369 A1 US 20170081369A1 US 201615368080 A US201615368080 A US 201615368080A US 2017081369 A1 US2017081369 A1 US 2017081369A1
Authority
US
United States
Prior art keywords
fmoc
tbu
trt
formula
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
US15/368,080
Other versions
US9957298B2 (en
Inventor
Caterina Bissantz
Konrad Bleichcher
Christophe Grundschober
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hoffmann La Roche Inc
Original Assignee
Hoffmann La Roche Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=50842169&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20170081369(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Hoffmann La Roche Inc filed Critical Hoffmann La Roche Inc
Publication of US20170081369A1 publication Critical patent/US20170081369A1/en
Assigned to HOFFMANN-LA ROCHE INC. reassignment HOFFMANN-LA ROCHE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: F. HOFFMANN-LA ROCHE AG
Assigned to F. HOFFMANN-LA ROCHE AG reassignment F. HOFFMANN-LA ROCHE AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BISSANTZ, CATERINA, BLEICHER, KONRAD, GRUNDSCHOBER, CHRISTOPHE
Application granted granted Critical
Publication of US9957298B2 publication Critical patent/US9957298B2/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/16—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to compounds of formula
  • the present compounds are oxytocin receptor agonists, which compounds are oxytocin analogs that retain oxytocin bioactivity. Such analog molecules are capable of acting in a manner similar to endogenous oxytocin, including binding the oxytocin receptor. Analogs of oxytocin have completely new molecular structures.
  • Oxytocin is a nine amino acid cyclic peptide hormone with two cysteine residues that form a disulfide bridge between position 1 and 6.
  • Human oxytocin comprises the sequence Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly.
  • Peptides have emerged as a commercially relevant class of drugs that offer the advantage of greater specifity and potency and lower toxicity profiles over traditional small molecule pharmaceuticals. They offer promising treatment options for numerous diseases, such as diabetes, HIV, hepatitis, cancer and others, with physicians and patents becoming more accepting of peptide-based medicines.
  • the present invention relates to peptidic oxytocin receptor agonists, which also include the natural hormone oxytocin and carbetocin.
  • Oxytocin is a potent uterotonic agent for the control of uterine atony and excessive bleeding, clinically used to induce labour, and has been shown to enhance the onset and maintenance of lactation (Gimpl et al., Physiol. Rev., 81, (2001), 629-683, Ruis et al., BMJ, 283, (1981), 340-342).
  • Carbetocin (1-deamino-1-carba-2-tyrosine (O-methyl)-oxytocin) is also a potent uterotonic agent clinically used for the control of uterine atony and excessive bleeding.
  • Peptidic oxytocin agonists may be used for the treatment of Prader-Willi Syndrome, which is a rare genetic disorder which affects one child in 25,000.
  • oxytocin agonists are useful for the treatment of inflammation and pain, including abdominal and back pain (Yang, Spine, 19, 1994, 867-71), sexual dysfunction in both male (Lidberg et al., Pharmakopsychiat., 10, 1977, 21-25) and female (Anderson-Hunt, et al., BMJ, 309, 1994, 929), irretable bowel syndrome (IBS, Louvel et al., Gut, 39, 1996, 741-47), constipation and gastrointestinal obstruction (Ohlsson et al., Neurogastroenterol.
  • oxytocin agonists may be useful for the diagnosis of both cancer and placental insufficiency.
  • Oxytocin and its receptors exists in areas of the brain implicated in the symptoms of schizophrenia, such as the nucleus accumbens and the hippocampus.
  • the oxytocin receptor agonists may be used for the treatment of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, Alzheimer's disease, psychiatric disorders, memory loss and metabolic diseases (WO2012/016229).
  • Objects of the present invention are novel compounds of formula I and the use of compounds of formula I and their pharmaceutically acceptable salts for the treatment of CNS diseases related to the oxytocin receptor, which diseases are autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal,drug addiction and for the treatment of Prader-Willi Syndrome.
  • the present invention may provide selective, efficacious compounds, providing alternatives and/or improvements in the treatment of certain CNS diseases including autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.
  • CNS diseases including autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.
  • the present peptides have a very good selectivity to the vasopressin receptors V1a and V2 as shown in the table. This may have a major advantage for use as medicament to avoid side effects. These physiological effects may be considered to be undesirable side effects in the case of medicines aimed at treating diseases of the central nervous system. Therefore it is desirable to obtain medicines having selectivity for the oxytocin receptor vs vasopressin receptor.
  • lower alkyl denotes a saturated straight- or branched chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like.
  • lower alkyl substituted by hydroxy denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a hydroxy group.
  • cycloalkyl denotes a cyclic alkyl chain, containing from 3 to 6 carbon atoms.
  • the term “five-membered aromatic heterocyclic group” denotes an imidazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl or isoxazolyl group.
  • pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • the preferred five-membered heterocyclic ring is an imidazole ring.
  • a further embodiment are compounds of formula I, wherein R 1 is methyl or cyclopropyl.
  • a furher embodiment are compounds of formula I, wherein R 1 and R 2 may form together with the N and C atom to which they are attached a pyrrolidine ring.
  • the compounds herein were synthesized by standard methods in solid phase peptide chemistry utilizing both Fmoc and Boc methodology. Reactions carried out manually were performed at room temperature, while microwave assisted peptide synthesis was performed at elevated temperature.
  • the cyclic peptides can be generated either via on-bead cyclisation (Allyl/Aloc strategy METHOD A) or as fully deprotected linear peptides via solution phase cyclisation (METHOD B).
  • Linear peptides were either synthesized manually or using microwave technology via state-of-the-art solid phase synthesis protocols (Fmoc-chemistry) as referenced by e.g.: Kates and Albericio, Eds., “Solid Phase Synthesis: A practical guide”, Marcel Decker, New York, Basel, 2000.
  • Fmoc-chemistry state-of-the-art solid phase synthesis protocols
  • TentaGel-S-RAM resin (0.24 meq/g) was used. All Fmoc-amino acids were added in a 4-fold excess after activation with HOBT/HBTU 1:1 (0.5 mol/L in DMF) and 4 eq of DIPEA (2 mol/L in NMP). Fmoc-cleavage was achieved with 20% Piperidine in DMF.
  • METHOD A The resin-linked peptides were treated manually with a solution of 20 eq phenylsilane in DCM and 0.05 eq of tetrakis triphenylphosphine palladium for 30 min at RT. This procedure was repeated. The resin was washed with a solution of 0.5% sodium dithiocarbamate in DMF. For the on-bead lactam formation, again activation reagent was added to the resin and shaken for additional 8 h at RT. Completion of cyclisation was verified via Ninhydrin-test.
  • METHOD B Peptides were cyclized in solution after deprotection and cleavage from the resin and standard work-up. Crude peptides were treated with standard peptide activation regents in DMF. The cyclisation was monitored via HPLC.
  • a cleavage-cocktail of trifluoroacetic acid, triisopropylsilane and water (95/2.5/2.5) was added to the resin and shaken for 1 h at RT.
  • Cleaved peptides were precipitated in cold Ether ( ⁇ 18° C.).
  • the peptides were centrifuged and the residue washed twice with cold ether.
  • the residues were again dissolved in water/acetonitrile and lyophilized.
  • Peptides were purified using reversed phase high performance liquid chromatography (RP-HPLC) using a Reprospher 100 C18-T Columm (100 ⁇ 4.6 mm, 5u particle size) as a stationary phase and water/acetonitrile as eluent
  • RP-HPLC reversed phase high performance liquid chromatography
  • the peptide was synthesized using CEM Microwave technology with coupling times of 5 minutes per amino acid at elevated temperature (78° C.) and a 0.25 mmol scale.
  • the synthesis is carried out using the TentalGel-S RAM resin as a solid support (0.24 meq/g). All amino acids used were dissolved in DMF to 0.2 mol concentration.
  • a mixture of HOBT/HBTU 1:1 (0.5 mol/L) 4 eq. and DIPEA 4eq. was used to activate the amino acids.
  • Fmoc-Cleavage was achieved with Piperidine in DMF (20%) for 3 min. Fmoc-cleavage was repeated.
  • the resin was treated manually with a solution of 20 eq. phenyl silane and 0.05 eq. of tetrakis triphenylphosphine palladium in DCM (5 ml) for 30 min at RT. This procedure was repeated. The resin was washed with a solution of 0.5% sodium dithiocarbamate in DMF twice. The washing step was repeated with DCM.
  • the crude peptide was purified by preparative HPLC on a Reprospher 100 C18-T Columm (100 ⁇ 4.6 mm, 5 um particle size). As eluent system a mixture of 0.1% TFA/water/acetonitrile was used with a gradient of 0-50% acetonitrile within 0-30 min. The fractions were collected and checked by analytical HPLC. Fractions containing pure product were combined and lyophilized. 7.2 mg of white powder were obtained.
  • the stable cell lines were grown in F-12 K Nutrient Mixture (Kaighns Modification), containing 10% foetal bovine serum (FBS), 1% penicillin-streptomycin, 1% L-glutamate, 200 ug/ml Geneticin at 37° C. in a 10% CO 2 incubator at 95% humidity.
  • FBS foetal bovine serum
  • penicillin-streptomycin 1% L-glutamate
  • Geneticin at 37° C. in a 10% CO 2 incubator at 95% humidity.
  • the existing culture media was removed from the wells and 100 ⁇ l of the dye-loading buffer was added to each well and incubated for approximately 60 min at 37° C. in a 5% CO 2 incubator at 95% humidity. Once dye-loaded, the cells were washed thoroughly on an Embla cell washer with the assay buffer to remove any unincorporated dye. Exactly 100 ⁇ l assay buffer was left in each well.
  • Each 96 well plate containing dye-loaded cells was placed into the FLIPR machine and the laser intensity set to a suitable level to detect low basal fluorescence.
  • 25 ⁇ l diluted compound was added to the plate 10 seconds into the fluorescent measurements and fluorescent response was recorded for 5 minutes.
  • the fluorescence data was normalized to the endogenous full agonist dose-response set at 100% for the maximum response and 0% for the minimum.
  • the concentration of agonist that produced a half-maximal response is represented by the EC 50 value, the logarithm of which yielded the pEC 50 value.
  • the compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations.
  • the pharmaceutical preparations can be administered preferably transdermal, intranasal, subcutaneous or intra venous (iv).
  • Transdermal is a route of administration wherein active ingredients are delivered across the skin for systematic distribution. Examples include transdermal patches used for medicine delivery, and transdermal implants used for medical or aesthetic purposes.
  • Nasal administration can be used to deliver drugs for either local or systemic effects, nasal sprays for local effect are quite common.
  • Peptide drugs may be administered as nasal sprays to avoid drug degradation after oral administration.
  • Subcutaneous injections are also common for the administration of peptide drugs.
  • An intramuscular injection is the injection of a substance directly into the muscle. It is one of several alternative methods for the administration of medications. It is often used for particular forms of medication that are administered in small amounts. The injections should be given under the skin.
  • the intravenous route is the infusion of liquid substances directly into a vein. Compared with other routes of administration, the intravenous route is the fastest way to deliver fluids and medications throughout the body.
  • the pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • the most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory, loss alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.
  • the dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
  • the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof.
  • the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

Abstract

The present compounds compounds are oxytocin receptor agonists for the treatment of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.

Description

    CROSS REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of International Application No. PCT/EP2015/062054, having an international filing date of 1 Jun. 2015, the entire contents of which are incorporated herein by reference, and which claims benefit under 35 U.S.C. 119 to European Patent Application No. 14170992.3, filed 3 Jun. 2014, the entire contents of which are incorporated herein by reference.
  • The invention relates to compounds of formula
  • Figure US20170081369A1-20170323-C00001
  • wherein
    • R1 is hydrogen, lower alkyl or cycloalkyl;
    • R2 is hydrogen or
    • R1 and R2 may form together with the N and C atom to which they are attached a pyrrolidine ring optionally substituted by one or two F-atoms or by hydroxy, or may form an azetidine or a piperazine ring;
    • R3 is hydrogen, lower alkyl, lower alkyl substituted by hydroxy, —(CH2)2C(O)NH2, benzyl, phenyl, —CH2-five membered aromatic heterocyclic group, CH2-indolyl, —CH2-cycloalkyl, cycloalkyl or —(CH2)2—S-lower alkyl;
    • is hydrogen or lower alkyl; or
    • X is —C(O)—CHR4—CHR4—C(O)—NH—CH2—
    • R4/R4′ are hydrogen or one of R4 or R4′ is amino:
    • o is 0 or 1;
      or to pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof.
  • It has been found that the present compounds are oxytocin receptor agonists, which compounds are oxytocin analogs that retain oxytocin bioactivity. Such analog molecules are capable of acting in a manner similar to endogenous oxytocin, including binding the oxytocin receptor. Analogs of oxytocin have completely new molecular structures.
  • Oxytocin is a nine amino acid cyclic peptide hormone with two cysteine residues that form a disulfide bridge between position 1 and 6. Human oxytocin comprises the sequence Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly.
  • Peptides have emerged as a commercially relevant class of drugs that offer the advantage of greater specifity and potency and lower toxicity profiles over traditional small molecule pharmaceuticals. They offer promising treatment options for numerous diseases, such as diabetes, HIV, hepatitis, cancer and others, with physicians and patents becoming more accepting of peptide-based medicines. The present invention relates to peptidic oxytocin receptor agonists, which also include the natural hormone oxytocin and carbetocin.
  • Oxytocin is a potent uterotonic agent for the control of uterine atony and excessive bleeding, clinically used to induce labour, and has been shown to enhance the onset and maintenance of lactation (Gimpl et al., Physiol. Rev., 81, (2001), 629-683, Ruis et al., BMJ, 283, (1981), 340-342). Carbetocin (1-deamino-1-carba-2-tyrosine (O-methyl)-oxytocin) is also a potent uterotonic agent clinically used for the control of uterine atony and excessive bleeding.
  • Peptidic oxytocin agonists may be used for the treatment of Prader-Willi Syndrome, which is a rare genetic disorder which affects one child in 25,000.
  • Further research indicates that oxytocin agonists are useful for the treatment of inflammation and pain, including abdominal and back pain (Yang, Spine, 19, 1994, 867-71), sexual dysfunction in both male (Lidberg et al., Pharmakopsychiat., 10, 1977, 21-25) and female (Anderson-Hunt, et al., BMJ, 309, 1994, 929), irretable bowel syndrome (IBS, Louvel et al., Gut, 39, 1996, 741-47), constipation and gastrointestinal obstruction (Ohlsson et al., Neurogastroenterol. Motil., 17, 2005, 697-704), autism (Hollander et al., Neuropsychopharm., 28, 2008, 193-98), stress, including post traumatic stress disorder (PTSD) (Pitman et al., Psychiatry Research, 48, 107-117), anxiety, including anxiety disorders and depression (Kirsch et al., J. Neurosci., 25, 49, 11489-93, Waldherr et al., PNAS, 104, 2007, 16681-84), surgical blood loss or control of post-partum haemorrhage (Fujimoto et al., Acta Obstet. Gynecol., 85, 2006, 1310 -14), labor induction and maintenance (Flamm et al., Obstet. Gynecol., 70, 1987, 70-12), wound healing and infection, mastitis and placenta delivery, and osteoporosis. Additionally, oxytocin agonists may be useful for the diagnosis of both cancer and placental insufficiency.
  • Furthermore, the Articles “Intranasal Oxytocin blocks alcohol withdrawal in human subjects” (Alcohol Clin Exp Res, Vol, No. 2012) and “Breaking the loop: Oxytocin as a potential treatment for drug addiction” (Hormones and Behavior, 61, 2012, 331-339) propose to treat alcohol withdrawal and drug addiction with a oxytocin agonist.
  • Oxytocin and its receptors exists in areas of the brain implicated in the symptoms of schizophrenia, such as the nucleus accumbens and the hippocampus. The oxytocin receptor agonists may be used for the treatment of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, Alzheimer's disease, psychiatric disorders, memory loss and metabolic diseases (WO2012/016229).
  • Objects of the present invention are novel compounds of formula I and the use of compounds of formula I and their pharmaceutically acceptable salts for the treatment of CNS diseases related to the oxytocin receptor, which diseases are autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal,drug addiction and for the treatment of Prader-Willi Syndrome.
  • Further objects are the preparation of novel compounds of formula I and medicaments, containing them.
  • The present invention may provide selective, efficacious compounds, providing alternatives and/or improvements in the treatment of certain CNS diseases including autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory loss, alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.
  • It has been shown that the present peptides have a very good selectivity to the vasopressin receptors V1a and V2 as shown in the table. This may have a major advantage for use as medicament to avoid side effects. These physiological effects may be considered to be undesirable side effects in the case of medicines aimed at treating diseases of the central nervous system. Therefore it is desirable to obtain medicines having selectivity for the oxytocin receptor vs vasopressin receptor.
  • As used herein, the term “lower alkyl” denotes a saturated straight- or branched chain group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like.
  • The term “lower alkyl substituted by hydroxy” denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by a hydroxy group.
  • The term “cycloalkyl” denotes a cyclic alkyl chain, containing from 3 to 6 carbon atoms.
  • As used herein, the term “five-membered aromatic heterocyclic group” denotes an imidazolyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, oxadiazolyl or isoxazolyl group.
  • The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
  • The preferred five-membered heterocyclic ring is an imidazole ring.
  • Preferred are compounds of formula I, wherein o is 0.
  • A further embodiment are compounds of formula I, wherein R1 is methyl or cyclopropyl.
  • A furher embodiment are compounds of formula I, wherein R1 and R2 may form together with the N and C atom to which they are attached a pyrrolidine ring.
  • The following specific compounds have been prepared and tested for their agonistic activity on the oxytocin receptor:
  • Figure US20170081369A1-20170323-C00002
    Figure US20170081369A1-20170323-C00003
    Figure US20170081369A1-20170323-C00004
    Figure US20170081369A1-20170323-C00005
    Figure US20170081369A1-20170323-C00006
    Figure US20170081369A1-20170323-C00007
    Figure US20170081369A1-20170323-C00008
    Figure US20170081369A1-20170323-C00009
    Figure US20170081369A1-20170323-C00010
    Figure US20170081369A1-20170323-C00011
    Figure US20170081369A1-20170323-C00012
    Figure US20170081369A1-20170323-C00013
  • The compounds herein were synthesized by standard methods in solid phase peptide chemistry utilizing both Fmoc and Boc methodology. Reactions carried out manually were performed at room temperature, while microwave assisted peptide synthesis was performed at elevated temperature.
    • General Synthesis Description:
  • The cyclic peptides can be generated either via on-bead cyclisation (Allyl/Aloc strategy METHOD A) or as fully deprotected linear peptides via solution phase cyclisation (METHOD B).
  • Linear peptides were either synthesized manually or using microwave technology via state-of-the-art solid phase synthesis protocols (Fmoc-chemistry) as referenced by e.g.: Kates and Albericio, Eds., “Solid Phase Synthesis: A practical guide”, Marcel Decker, New York, Basel, 2000. As a solid support TentaGel-S-RAM resin (0.24 meq/g) was used. All Fmoc-amino acids were added in a 4-fold excess after activation with HOBT/HBTU 1:1 (0.5 mol/L in DMF) and 4 eq of DIPEA (2 mol/L in NMP). Fmoc-cleavage was achieved with 20% Piperidine in DMF.
    • Allyl/Aloc-Cleavage & Lactam-Cyclisation:
  • METHOD A: The resin-linked peptides were treated manually with a solution of 20 eq phenylsilane in DCM and 0.05 eq of tetrakis triphenylphosphine palladium for 30 min at RT. This procedure was repeated. The resin was washed with a solution of 0.5% sodium dithiocarbamate in DMF. For the on-bead lactam formation, again activation reagent was added to the resin and shaken for additional 8 h at RT. Completion of cyclisation was verified via Ninhydrin-test.
  • METHOD B: Peptides were cyclized in solution after deprotection and cleavage from the resin and standard work-up. Crude peptides were treated with standard peptide activation regents in DMF. The cyclisation was monitored via HPLC.
    • Cleavage & Work-Up:
  • A cleavage-cocktail of trifluoroacetic acid, triisopropylsilane and water (95/2.5/2.5) was added to the resin and shaken for 1 h at RT. Cleaved peptides were precipitated in cold Ether (−18° C.). The peptides were centrifuged and the residue washed twice with cold ether. The residues were again dissolved in water/acetonitrile and lyophilized.
    • Purification:
  • Peptides were purified using reversed phase high performance liquid chromatography (RP-HPLC) using a Reprospher 100 C18-T Columm (100×4.6 mm, 5u particle size) as a stationary phase and water/acetonitrile as eluent
  • (Gradient 1-50% MeCN over 30 min). Fractions were collected and analyzed by LC/MS. Pure product samples were combined and lyophilized. All peptides were obtained as white powders with a purity >85%. Product identification was obtained via mass spectrometry.
  • All standard amino acids were purchased from CEM. Fmoc-SAR-OH and Fmoc-N-Cyclopropyl-Glycine were purchased from Bachem and Enamine respectively. Mono-tBu-Succinate were purchased from Sigma-Aldrich
    • Synthesis of Mono-Allyl Succinate:
  • A solution of 46 mmol of 4-tert-butoxy-4-oxobutanoic acid (Sigma-Aldrich) in 70 ml THF and 92 mmol DIPEA was cooled 0° C. Now a solution of 55 mmol of 3-iodoprop-1-ene (Fluka) in 6 ml of THF was added dropwise and warmed up to RT and stirred overnight. The reaction mixture was extracted with aqueous bicarbonate, dried over sodium sulfate and the solvent evaporated. 3.7 g of brown oil was obtained. Crude material was purified via Kieselgel chromatography to yield 3.4 g of di-ester. The intermediate was dissolved in 10 ml DCM and 5 ml of TFA added at RT and stirred overnight. Solvent and TFA were evaporated to yield 1.6 g of final product.
  • The detailed description for the synthesis of example 1 is provided to further illustrate the synthesis conditions:
    • Peptide Synthesis:
  • The peptide was synthesized using CEM Microwave technology with coupling times of 5 minutes per amino acid at elevated temperature (78° C.) and a 0.25 mmol scale. The synthesis is carried out using the TentalGel-S RAM resin as a solid support (0.24 meq/g). All amino acids used were dissolved in DMF to 0.2 mol concentration. A mixture of HOBT/HBTU 1:1 (0.5 mol/L) 4 eq. and DIPEA 4eq. was used to activate the amino acids. Fmoc-Cleavage was achieved with Piperidine in DMF (20%) for 3 min. Fmoc-cleavage was repeated.
    • Aloc-& Allyl-Cleavage:
  • The resin was treated manually with a solution of 20 eq. phenyl silane and 0.05 eq. of tetrakis triphenylphosphine palladium in DCM (5 ml) for 30 min at RT. This procedure was repeated. The resin was washed with a solution of 0.5% sodium dithiocarbamate in DMF twice. The washing step was repeated with DCM.
    • On-Bead Cyclisation (Method A):
  • Again coupling-reagent (4 ml of an 0.5 mol/L solution HOBT/HBTU (1:1) and 1 ml of DIPEA (4 eq.) in DMF was added to the resin. The slurry was shaken for about 8 h at RT. The resin was washed with DMF and DCM twice. Completion of cyclisation was verified via Ninhydrin test.
  • Cleavage from Resin:
  • 10 ml of the cleavage-cocktail (TFA; TIS; water (95/2.5/2.5)) was added to the resin and shaken for 1 h at RT. Cleaved peptide was precipitated in cold ether (−18° C.). The peptide was centrifuged and the precipitates washed twice with cold ether. The precipitate was dissolved in H2O/Acetonitrile and lyophilized to yield 210 mg white powder.
  • All other analogues were generated upon Method B using the off-bead cyclisation strategy.
    • Off-Bead Cyclisation (Method B):
  • Crude peptide was dissolved in DMF (15 ml). 1 eq of coupling reagents PyaOP (0.5 mol/L) in DMF and DIPEA in NMP (2 mol/l) were added. The reaction mixture was stirred at RT for 1 h. After the reaction was completed (LCMS control) the DMF content was concentrated down to approximately 2 ml. The residue was precipitated in cold (−18° C.) diethyl ether (40 ml). The peptide was centrifuged and the precipitate washed with cold ether.
    • Purification:
  • The crude peptide was purified by preparative HPLC on a Reprospher 100 C18-T Columm (100×4.6 mm, 5 um particle size). As eluent system a mixture of 0.1% TFA/water/acetonitrile was used with a gradient of 0-50% acetonitrile within 0-30 min. The fractions were collected and checked by analytical HPLC. Fractions containing pure product were combined and lyophilized. 7.2 mg of white powder were obtained.
  • All other peptides listed below were synthesized accordingly.
    • Abbreviations:
    • Fmoc: 9-Fluorenylmethoxycarbonyl
    • tBu: tert. Butyl
    • Gly: Glycine
    • Phe: Phenylalanine
    • Cha: Cyclohexylalanine
    • Chg: Cyclohexylglycine
    • CyclopropGly: N-Cyclopropylglycine
    • Sar: Sarcosine
    • Ile: Isoleucine
    • Leu: Leucine
    • Nle: Norleucin
    • Nva: Norvaline
    • Aib: Aminoisobutyric Acid
    • Pro: Proline
    • Ala: Alanine
    • Val: Valine
    • homoVal: Homovaline
    • MeVal: L-α-Methyl-Valine
    • His(Trt): sidechain-protected (Trityl) Histidine
    • Asn(Trt): sidechain-protected (Trityl)Asparagine
    • Gln(Trt): sidechain-protected (Trityl) Glutamine
    • Ser(tBu): sidechain-protected (tert. Butyl) Serine
    • Tyr(tBu): sidechain-protected (tBu)Tyrosine
    • Thr(tBu): sidechain-protected (tBu) Threonine
    • HOBT: N-Hydroxybenzotriazole
    • COMU: 1-[(1-(Cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethyl aminomorpholino)] uronium hexafluorophosphate
    • PyoAP: (7-Azabenzotriazol-1yloxy) tripyrrolidino-phosphonium hexaflourophosphate
    • HBTU: O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate
    • DMF: N,N-Dimethylformamide
    • NMP: N-Methylpyrrolidone
    • DIPEA: N,N-Diisopropylamine
    • DCM: Dichlormethane
    • MeCN: Acetonitril
    EXAMPLE 1
  • Figure US20170081369A1-20170323-C00014
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 971.1; observed 971.2
    • EXAMPLE 2
  • Figure US20170081369A1-20170323-C00015
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Sar-OH, Fmoc-Dap(Aloc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and Fmoc-Asp(Allyl)-OH. MS (M+H+): expected 960.0; observed 960.8
    • EXAMPLE 3
  • Figure US20170081369A1-20170323-C00016
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 945.0; observed 945.5
    • EXAMPLE 4
  • Figure US20170081369A1-20170323-C00017
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-SAR-OH, Fmoc-Dap(Aloc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH, Fmoc-D-AspOAllyl. MS (M+H+): expected 960.0; observed 960.8
    • EXAMPLE 5
  • Figure US20170081369A1-20170323-C00018
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 931.0; observed 931.1
    • EXAMPLE 6
  • Figure US20170081369A1-20170323-C00019
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nva-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 945.0; observed 945.2
    • EXAMPLE 7
  • Figure US20170081369A1-20170323-C00020
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeVal-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 985.0; observed 985.2
    • EXAMPLE 8
  • Figure US20170081369A1-20170323-C00021
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Met-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 989.1; observed 989.5
    • EXAMPLE 9
  • Figure US20170081369A1-20170323-C00022
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 971.0; observed 971.5
    • EXAMPLE 10
  • Figure US20170081369A1-20170323-C00023
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thr(tBu)-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 959.0; observed 959.5
    • EXAMPLE 11
  • Figure US20170081369A1-20170323-C00024
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 945.0; observed 945.5
    • EXAMPLE 12
  • Figure US20170081369A1-20170323-C00025
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 957.0; observed 957.6
    • EXAMPLE 13
  • Figure US20170081369A1-20170323-C00026
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Gln(Trt)-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 986.0; observed 986.5
    • EXAMPLE 14
  • Figure US20170081369A1-20170323-C00027
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-PheOH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 1005.0; observed 1006.8
    • EXAMPLE 15
  • Figure US20170081369A1-20170323-C00028
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-His(Trt)OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 995.0; observed 996.7
    • EXAMPLE 16
  • Figure US20170081369A1-20170323-C00029
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Trp(Boc)-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 1044.10; observed 1045.4
    • EXAMPLE 17
  • Figure US20170081369A1-20170323-C00030
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nva-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 957.0; observed 957.5
    • EXAMPLE 18
  • Figure US20170081369A1-20170323-C00031
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Cha-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 1011.1; observed 1011.5
    • EXAMPLE 19
  • Figure US20170081369A1-20170323-C00032
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Phg-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 991.0; observed 991.5
    • EXAMPLE 20
  • Figure US20170081369A1-20170323-C00033
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 997.0; observed 997.5
    • EXAMPLE 21
  • Figure US20170081369A1-20170323-C00034
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thi-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 1011.1; observed 1011.4
    • EXAMPLE 22
  • Figure US20170081369A1-20170323-C00035
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-homoLeu-OH, Fmoc-Pro-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 985.1; observed 985.5
    • EXAMPLE 23
  • Figure US20170081369A1-20170323-C00036
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeLeu-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 959.0; observed 959.5
    • EXAMPLE 24
  • Figure US20170081369A1-20170323-C00037
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 971.0; observed 971.2
    • EXAMPLE 25
  • Figure US20170081369A1-20170323-C00038
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-homoLeu-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 959.0; observed 959.1
    • EXAMPLE 26
  • Figure US20170081369A1-20170323-C00039
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Met-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 963.1; observed 963.6
    • EXAMPLE 27
  • Figure US20170081369A1-20170323-C00040
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Nva-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 931.0; observed 931.5
    • EXAMPLE 28
  • Figure US20170081369A1-20170323-C00041
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 945.0; observed 945.5
    • EXAMPLE 29
  • Figure US20170081369A1-20170323-C00042
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thr(tBu)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 933.0; observed 933.6
    • EXAMPLE 30
  • Figure US20170081369A1-20170323-C00043
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 919.0; observed 919.4
    • EXAMPLE 31
  • Figure US20170081369A1-20170323-C00044
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Cha-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 985.1; observed 985.6
    • EXAMPLE 32
  • Figure US20170081369A1-20170323-C00045
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Gln(Trt)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 960.0; observed 960.8
    • EXAMPLE 33
  • Figure US20170081369A1-20170323-C00046
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Phe-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 979.0; observed 979.3
    • EXAMPLE 34
  • Figure US20170081369A1-20170323-C00047
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thi-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 985.1; observed 985.6
    • EXAMPLE 35
  • Figure US20170081369A1-20170323-C00048
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 969.0; observed 969.9
    • EXAMPLE 36
  • Figure US20170081369A1-20170323-C00049
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Trp(Boc)-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 1018.0; observed 1018.6
    • EXAMPLE 37
  • Figure US20170081369A1-20170323-C00050
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Phg-OH, Fmoc-Sar-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate. MS (M+H+): expected 965.0; observed 965.2
    • EXAMPLE 38
  • Figure US20170081369A1-20170323-C00051
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.
  • MS (M+H+): expected 971.1; observed 971.8
    • EXAMPLE 39
  • Figure US20170081369A1-20170323-C00052
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-MeVal-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.
  • MS (M+H+): expected 985.1; observed 985.6
    • EXAMPLE 40
  • Figure US20170081369A1-20170323-C00053
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Val-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.
  • MS (M+H+): expected 957.0; observed 957.5
    • EXAMPLE 41
  • Figure US20170081369A1-20170323-C00054
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Aib-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.
  • MS (M+H+): expected 943.0; observed 943.5
    • EXAMPLE 42
  • Figure US20170081369A1-20170323-C00055
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ile-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.
  • MS (M+H+): expected 971.1; observed 971.6
    • EXAMPLE 43
  • Figure US20170081369A1-20170323-C00056
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Chg-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.
  • MS (M+H+): expected 997.1; observed 997.6
    • EXAMPLE 44
  • Figure US20170081369A1-20170323-C00057
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Thr(tBu)-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.
  • MS (M+H+): expected 959.0; observed 959.5
    • EXAMPLE 45
  • Figure US20170081369A1-20170323-C00058
  • The following amino acids were used: Fmoc-Gly-OH, Fmoc-Ser(tBu)-OH, Fmoc-CyclopropGly-OH, Fmoc-Dap(Boc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Ile-OH, Fmoc-Tyr(tBu)-OH and mono-tBu succinate.
  • MS (M+H+): expected 945.0; observed 945.5
    • Material and Methods Cell Culture and Stable Clone Production
  • Chines Hamster Ovary (CHO) cells were transfected with expression plasmids encoding either the human V1a, the human Oxytocin (OTR) or the human V2 receptor, the later in combination with the chimeric Gqs5 G protein to redirect the signal to Calcium flux. Stable cells were cloned by limiting dilution to yield monoclonal cell lines expressing either human V1a, human V2+Gqs5 or human OTR receptors and selected based on functional responses detected on a fluorometric imaging plate reader (FLIPR) detecting Calcium flux in the cell after receptor activation. The stable cell lines were grown in F-12 K Nutrient Mixture (Kaighns Modification), containing 10% foetal bovine serum (FBS), 1% penicillin-streptomycin, 1% L-glutamate, 200 ug/ml Geneticin at 37° C. in a 10% CO2 incubator at 95% humidity.
    • Calcium Flux Assays Using Fluorescent Imaging (Fluorometric Imaging Plate Reader, FLIPR)
  • On the afternoon before the assay, cells were plated at a density of 50,000 cells/well into black 96 well plates with clear bottoms to allow cell inspection and fluorescence measurements from the bottom of each well. The density of cells was sufficient to yield a confluent monolayer the next day. Hanks balanced salt solution, without phenol red, containing 20 mM HEPES (pH 7.3) and 2.5 mM probenecid (assay buffer) was prepared fresh for each experiment. Compound dilutions were made using a Beckman Biomek 2000 laboratory automation workstation, in assay buffer containing 1% DMSO. The dye-loading buffer consisted of a final concentration of 2 μM Fluo-4-AM (dissolved in DMSO and pluronic acid) in assay buffer. The existing culture media was removed from the wells and 100 μl of the dye-loading buffer was added to each well and incubated for approximately 60 min at 37° C. in a 5% CO2 incubator at 95% humidity. Once dye-loaded, the cells were washed thoroughly on an Embla cell washer with the assay buffer to remove any unincorporated dye. Exactly 100 μl assay buffer was left in each well.
  • Each 96 well plate containing dye-loaded cells was placed into the FLIPR machine and the laser intensity set to a suitable level to detect low basal fluorescence. To test compounds as agonists, 25 μl diluted compound was added to the plate 10 seconds into the fluorescent measurements and fluorescent response was recorded for 5 minutes. The fluorescence data was normalized to the endogenous full agonist dose-response set at 100% for the maximum response and 0% for the minimum. Each agonist concentration-response curve was constructed using a four parameter logistic equation with Microsoft Excel XLFit as follows: Y=Minimum+((Maximum−Minimum)/(1+10(LogEC50-X)nH)), where y is the % normalized fluorescence, minimum is the minimum y, maximum is the maximum y, logEC50 is the log10 concentration which produces 50% of the maximum induced fluorescence, x is the log10 of the concentration of the agonist compound and H is the slope of the curve (the Hill Coefficient). The maximum value gives the efficacy of the agonist test compound in percentage. The concentration of agonist that produced a half-maximal response is represented by the EC50 value, the logarithm of which yielded the pEC50 value.
  • The following EC50 (nM), and efficacy (%) for the specific peptides may be provided, together with comparative data for hV1a and hV2:
  • hOT hV2
    EC50(nM)/ hV1a EC50 (nM)/
    Expl. efficacy (%) EC50 (nM) efficacy (%)
    1 1/105  5125 216/130
    2 4/144 >27000 —
    3 0.9/113  >27000 612/130
    4 5/126 — —
    5 0.7/111  >27000 1126/123 
    6 1/119 >27000 364/104
    7 3/101 — —
    8 1/134 — —
    9 1/132 — —
    10 1/130 — —
    11 3/128 — —
    12 1.6/130  — —
    13 8/128 — —
    14 6/122 — —
    15 8/123 — —
    16 4/100 — —
    17 0.6/114    351 116/116
    18 2/130 — —
    19 0.4/114    470  59/114
    20 0.9/117    562 174/112
    21 4/126 — —
    22 0.8/109    391 176/106
    23 3/123 — —
    24 0.5/104  >27000 152/120
    25 0.8/103  >27000 213/118
    26 0.5/107  >27000 281/119
    27 0.8/107  >27000 282/114
    28 0.5/109  >27000 1385/119 
    29 0.6/109  >27000 2068/113 
    30 2/109 — —
    31 0.5/107  >27000 199/126
    32 5/112 — —
    33 3/111 — —
    34 3/106 — —
    35 4/111 — —
    36 2/111 — —
    37 0.2/112  >27000  53/121
    38 0.38/126   >27000 626/146
    39 1.3/108  — —
    40 0.6/106  — —
    41 2.5/108  — —
    42 0.37/115   — —
    43 0.26/110   — —
    44 0.9/115  — —
    45 0.8/117  — —
  • The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered preferably transdermal, intranasal, subcutaneous or intra venous (iv).
  • Transdermal is a route of administration wherein active ingredients are delivered across the skin for systematic distribution. Examples include transdermal patches used for medicine delivery, and transdermal implants used for medical or aesthetic purposes.
  • Nasal administration can be used to deliver drugs for either local or systemic effects, nasal sprays for local effect are quite common. Peptide drugs may be administered as nasal sprays to avoid drug degradation after oral administration.
  • Subcutaneous injections are also common for the administration of peptide drugs. An intramuscular injection is the injection of a substance directly into the muscle. It is one of several alternative methods for the administration of medications. It is often used for particular forms of medication that are administered in small amounts. The injections should be given under the skin.
  • The intravenous route is the infusion of liquid substances directly into a vein. Compared with other routes of administration, the intravenous route is the fastest way to deliver fluids and medications throughout the body.
  • The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
  • The most preferred indications in accordance with the present invention are those which include disorders of the central nervous system, for example the treatment or prevention of autism, stress, including post traumatic stress disorder, anxiety, including anxiety disorders and depression, schizophrenia, psychiatric disorders and memory, loss alcohol withdrawal, drug addiction and for the treatment of Prader-Willi Syndrome.
  • The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. The dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

Claims (10)

1. A compound of formula
Figure US20170081369A1-20170323-C00059
wherein
R1 is hydrogen, lower alkyl or cycloalkyl;
R2 is hydrogen or
R1 and R2 may form together with the N and C atom to which they are attached a pyrrolidine ring optionally substituted by one or two F-atoms or by hydroxy, or may form an azetidine or a piperazine ring;
R3 is hydrogen, lower alkyl, lower alkyl substituted by hydroxy, —(CH2)2C(O)NH2, benzyl, phenyl, —CH2-five membered aromatic heterocyclic group, CH2-indolyl, —CH2-cycloalkyl, cycloalkyl or —(CH2)2-S-lower alkyl;
R3′ is hydrogen or lower alkyl; or
X is —C(O)—CHR4—CHR4′—C(O)—NH—CH2—
R4/R4′ are hydrogen or one of R4 or R4′ is amino:
o is 0 or 1;
or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof.
2. A compound of formula I according to claim 1, wherein R1 is methyl or cyclopropyl.
3. A compound of formula I according to claim 1, wherein R1 and R2 may form together with the N and C atom to which they are attached a pyrrolidine ring.
4. A compound of formula I according to claim 1, wherein o is 0.
5. A compound of formula I according to claim 1, selected from the group consisting of
Figure US20170081369A1-20170323-C00060
Figure US20170081369A1-20170323-C00061
Figure US20170081369A1-20170323-C00062
Figure US20170081369A1-20170323-C00063
Figure US20170081369A1-20170323-C00064
Figure US20170081369A1-20170323-C00065
Figure US20170081369A1-20170323-C00066
Figure US20170081369A1-20170323-C00067
Figure US20170081369A1-20170323-C00068
Figure US20170081369A1-20170323-C00069
Figure US20170081369A1-20170323-C00070
Figure US20170081369A1-20170323-C00071
6. A pharmaceutical composition comprising a compound of formula I according to claim 1, and a pharmaceutical acceptable carrier and/or adjuvant.
7. A method of inhibiting the oxytocin receptor in a cell, comprising administering to the cell a compound of formula I according to claim 1.
8. A method of treating a disorder selected from autism, stress, an anxiety disorder, depression, schizophrenia, a psychiatric disorder, memory loss, alcohol withdrawal, drug addiction, or Prader-Willi Syndrome, comprising administering to a subject in need thereof a compound of formula I according to claim 1.
9. The method of claim 8, wherein the disorder is stress or an anxiety disorder.
10. The method of claim 9, wherein the disorder is post-traumatic stress disorder or anxiety.
US15/368,080 2014-06-03 2016-12-02 Peptides as oxytocin agonists Expired - Fee Related US9957298B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP14170992 2014-06-03
EP14170992.3 2014-06-03
EP14170992 2014-06-03
PCT/EP2015/062054 WO2015185467A1 (en) 2014-06-03 2015-06-01 Peptides as oxytocin agonists

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2015/062054 Continuation WO2015185467A1 (en) 2014-06-03 2015-06-01 Peptides as oxytocin agonists

Publications (2)

Publication Number Publication Date
US20170081369A1 true US20170081369A1 (en) 2017-03-23
US9957298B2 US9957298B2 (en) 2018-05-01

Family

ID=50842169

Family Applications (1)

Application Number Title Priority Date Filing Date
US15/368,080 Expired - Fee Related US9957298B2 (en) 2014-06-03 2016-12-02 Peptides as oxytocin agonists

Country Status (16)

Country Link
US (1) US9957298B2 (en)
EP (1) EP3151849B1 (en)
JP (1) JP6412170B2 (en)
KR (1) KR20170004013A (en)
CN (1) CN106414479B (en)
AU (1) AU2015270723A1 (en)
CA (1) CA2949173A1 (en)
CL (1) CL2016003095A1 (en)
CR (1) CR20160563A (en)
EA (1) EA030091B1 (en)
IL (1) IL248553A0 (en)
MX (1) MX2016015873A (en)
PE (1) PE20161559A1 (en)
PH (1) PH12016502232A1 (en)
SG (1) SG11201610073PA (en)
WO (1) WO2015185467A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10441627B2 (en) 2014-09-19 2019-10-15 Ferring B.V. Method of treating prader-willi syndrome
US10967040B2 (en) 2018-09-20 2021-04-06 Levo Therapeutics, Inc. Methods of treating prader-willi syndrome with carbetocin
US11207373B2 (en) 2018-09-20 2021-12-28 Levo Therapeutics, Inc. Agitation process for preparing a carbetocin drug product

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019060962A1 (en) * 2017-09-28 2019-04-04 The University Of Sydney Metabolite inspired selective oxytocin receptor agonists

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9701162D0 (en) * 1997-03-27 1997-03-27 Karolinska Innovations Ab New use II
KR20070022753A (en) * 2004-05-26 2007-02-27 화이자 인코포레이티드 Indazole and indolone derivatives and their use as pharmaceuticals
WO2008091555A2 (en) * 2007-01-22 2008-07-31 Gtx, Inc. Nuclear receptor binding agents
US8673841B2 (en) * 2008-03-31 2014-03-18 Ferring B.V. Oxytocin analogues
JP2012502948A (en) * 2008-09-23 2012-02-02 エフ．ホフマン−ラ ロシュ アーゲー Isoxazolo [4,5] pyridin-3-yl-piperazine derivatives useful as modulators of dopamine D3 receptors
KR101701533B1 (en) * 2009-05-05 2017-02-13 에프. 호프만-라 로슈 아게 Isoxazole-pyridazine derivatives
TWI463990B (en) * 2009-09-21 2014-12-11 Ferring Bv Oxytocin receptor agonists
ES2509270T3 (en) * 2009-10-01 2014-10-17 The University Of Sydney Therapy and alcoholism prevention
KR101819804B1 (en) 2012-12-21 2018-01-17 에프. 호프만-라 로슈 아게 Peptides as oxytocin agonists

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10441627B2 (en) 2014-09-19 2019-10-15 Ferring B.V. Method of treating prader-willi syndrome
US10967040B2 (en) 2018-09-20 2021-04-06 Levo Therapeutics, Inc. Methods of treating prader-willi syndrome with carbetocin
US11207373B2 (en) 2018-09-20 2021-12-28 Levo Therapeutics, Inc. Agitation process for preparing a carbetocin drug product
US11298399B2 (en) 2018-09-20 2022-04-12 Levo Therapeutics, Inc. Carbetocin drug product and process for preparing same
US11844764B2 (en) 2018-09-20 2023-12-19 Acadia Pharmaceuticals, Inc. Agitation process for preparing a carbetocin drug product

Also Published As

Publication number Publication date
IL248553A0 (en) 2016-12-29
PH12016502232A1 (en) 2017-01-09
EA201692404A1 (en) 2017-05-31
AU2015270723A1 (en) 2016-11-17
SG11201610073PA (en) 2016-12-29
WO2015185467A1 (en) 2015-12-10
CA2949173A1 (en) 2015-12-10
CR20160563A (en) 2017-01-06
JP6412170B2 (en) 2018-10-24
JP2017518311A (en) 2017-07-06
CN106414479A (en) 2017-02-15
EP3151849B1 (en) 2018-10-10
US9957298B2 (en) 2018-05-01
CN106414479B (en) 2021-08-03
KR20170004013A (en) 2017-01-10
MX2016015873A (en) 2017-03-27
CL2016003095A1 (en) 2017-06-16
EA030091B1 (en) 2018-06-29
EP3151849A1 (en) 2017-04-12
PE20161559A1 (en) 2017-01-12

Similar Documents

Publication Publication Date Title
US9868766B2 (en) Peptides as oxytocin agonists
EP3152225B1 (en) Peptides as oxytocin agonists
KR101558404B1 (en) Oxytocin analogues
RU2539692C2 (en) Oxytocin receptor agonists
US9957298B2 (en) Peptides as oxytocin agonists

Legal Events

Date Code Title Description
AS Assignment

Owner name: HOFFMANN-LA ROCHE INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:F. HOFFMANN-LA ROCHE AG;REEL/FRAME:043008/0333

Effective date: 20140724

Owner name: F. HOFFMANN-LA ROCHE AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BISSANTZ, CATERINA;BLEICHER, KONRAD;GRUNDSCHOBER, CHRISTOPHE;REEL/FRAME:043008/0289

Effective date: 20140707

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20220501